(1) The calmodulin-dependent protein phosphatase requires divalent metal ions such as Ni(II), Mn(II), Mg(II), etc. for expression of full catalytic activity. Two Ni(II) ions can bind to the phosphatase. The first Ni(II) ion binding leads to dramatic activation, whereas the second Ni(II) ion binding results in deactivation. The mechanism of Ni(II)-deactivation has been studied in detail, both experimental and theoretically. It involves an initial loose binding step (dissociation constant about 21 mM) and a subsequent conformational rearrangement (rate constant approximately 0.078 per min). Binding of Ca(II) to the B subunit is vital to activation of the catalytic A subunit by the first Ni(II) ion. The Ni(II) ion interaction with the phosphatase can be described by an overall mechanism in which the two Ni(II) ions combine with the enzyme in an ordered manner. (2) Phosphorylation of the calmodulin-dependent protein phosphatase by protein kinase C has been investigated in greater detail. Two moles of phosphate are incorporated per mole of phosphatase. One of the phosphoryl groups is dephosphorylated by a new Ca(II)-inhibited phosphatase. The phosphorylation and dephosphorylation of the enzyme appears to be tied to the release and sequestration of Ca(II) ion in vivo. (3) The Ca(II)-inhibited protein phosphatase has been purified about 1500-fold. The purity is estimated at about 60% and the MW approximately 40,0000.